Heart failure is a complex syndrome resulting from the inability of the heart to pump blood sufficient to meet the body's needs. Heart failure is a progressive disease most common in the elderly and usually caused by other diseases/conditions that gradually damage the heart such as coronary heart disease, damaged heart valves, external pressure around the heart, and cardiac muscle disease. The kidneys play an important role in compensating for the heart's inability to pump blood. Normally, healthy kidneys are responsible for various functions such as: removal of fluid and wastes; maintenance of blood pressure; maintenance of salt, water, electrolyte and acid-base balance; stimulation of red cell production (via the release of erythropoietin); and promotion of calcium absorption. In heart failure patients, the kidneys compensate for inadequate cardiac output by increasing the volume of circulating blood (by increasing sodium and water reabsorption, thereby decreasing urine output), and maintaining blood pressure. In the short term these compensatory mechanisms serve to increase cardiac performance. However in the long term they become maladaptive. Heart failure can lead to progressive renal dysfunction (referred to as “cardiorenal syndrome”) that is associated with increased morbidity and mortality. Together, cardiac and renal dysfunction lead to fluid overload, which is often manifested as excess lung fluid (pulmonary edema) and dyspnea.
The primary functional unit of the kidneys is called the “nephron.” Each kidney consists of about one million nephrons. In each nephron, a group of interconnected capillary loops, called the glomerulus, filters the blood and produces a fluid, called the filtrate. The filtrate is similar to blood plasma but contains very little total protein. Unlike large proteins (e.g. albumin), inorganic ions and low-molecular-weight organic solutes are freely filtered by the glomerulus into the filtrate. Since the inorganic ions and low-molecular-weight organic solutes are freely filtered, their concentrations in the filtrate are very similar to their concentration in blood plasma.
The filtrate leaving the glomerulus contains a combination of waste materials that need to be removed from the body, other solutes (e.g. electrolytes)—some of which need to be removed from the body and some of which need to be retained by the body, and water—most of which needs to be retained by the body. To affect the removal and retention these substances, the filtrate leaving the glomerulus empties into a tiny tube called a tubule. Several processes occur within the tubule, including filtration, reabsorption, and secretion. These processes affect proper removal and retention of the various solutes and water.
Most of the water and other solutes (e.g. glucose, electrolytes, bicarbonate) are reabsorbed as the filtrate moves though the tubule. The process of reabsorption is critical since without it, the body would quickly dehydrate and suffer electrolyte and pH imbalances. Reabsorption is particularly important in the process of sodium and water retention/excretion. As the filtrate moves through the lumen of the tubule, some positively charged sodium ions passively enter the surrounding tubular cells since the insides of tubular cells are negatively charged with respect to the lumen. After entering the tubular cells, the sodium ions are actively transported out into the interstitial fluid, and eventually reabsorbed back into the blood. The reabsorption of water occurs via osmosis, secondary to the reabsorption of sodium. The sodium and water not reabsorbed by the tubular cells pass through the tubule, along with other solutes (e.g. urea), thus producing urine.
In heart failure patients, decreased cardiac output leads to vasoconstriction and various neurohormonal signals, both of which direct the kidney to reabsorb more sodium and water. This, in turn, leads to fluid overload, as mentioned above. In order to counteract increased sodium and water retention, drugs such as diuretics can be used to block sodium transport or to block the hormonal signals that lead to increased sodium reabsorption. However, many heart failure patients become less responsive to diuretics over time, and diuretics can produce unwanted side effects, such as excess potassium excretion. Thus, it would be valuable to identify a method of diuresis that does not have the unwanted effects of the pharmaceutical diuretics currently available. Promoting diuresis via such an alternative method could benefit heart failure patients suffering from fluid overload, as well as patients suffering from fluid overload due to other etiologies (i.e. renal failure).